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Birmingham, UK
Dr. Kakar is Research Fellow, Dr. Lane is Lecturer in Medicine, and Dr. Lip is Professor of Cardiovascular Medicine, Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital.
Correspondence to: Professor Gregory Y. H. Lip, Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, England, UK; e-mail: g.y.h.lip{at}bham.ac.uk
Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice, and confers a substantial risk of stroke and thromboembolism. Anticoagulation with warfarin substantially reduces this risk, with an even greater benefit for secondary prevention.1 With the increasingly elderly population, AF is becoming even more prevalent, resulting in stroke prevention being an increasingly crucial public health target.
Many contemporary guidelines for AF management stress the importance of appropriate antithrombotic therapy as thromboprophylaxis.2 However, "to prescribe warfarin or not" is a dilemma that faces physicians in their routine everyday practice. The risk of stroke in AF is not homogeneous, and subjects at high risk of stroke can be identified using clinical criteria, with some refinement from echocardiography.3 Interest into the underlying pathophysiologic mechanisms leading to thromboembolism has generated prognostic data on prothrombotic indexes that may contribute to thrombogenesis in AF, and that may further refine clinical risk stratification for stroke and vascular events among AF patients.4
Despite clear guidelines, warfarin is still underused, with a prescription rate of only 15 to 44% among eligible patients.56 Physician perceptions of risk benefit are not always reliable, and bleeding risks are often overestimated.67 Moreover, bleeding risk is not inconsequential. For example, one large study8 in an elderly population reported a yearly incidence of 1.5% major bleeding events, of which 0.3% were intracranial hemorrhages. Appropriate assessment of the risk-benefit ratio of bleeding vs thromboprophylaxis with warfarin is therefore crucial.
Many risk factors for bleeding with concomitant warfarin therapy have been identified, and include the following: increasing age,910 female gender,8 high BP,11 anemia,8 myocardial infarction,1213 cerebrovascular disease,14 concomitant use of antiplatelet therapy,8 history of previous bleeding8 and concomitant medication use.15 Clearly, there are some inconsistencies, depending on the study population and clinical setting. The systematic reviews that informed the new evidence-based UK National Institute of Health and Clinical Excellence national clinical guideline for AF2 recommendations make clear that the assessment of bleeding risk should be part of the clinical assessment of patients before starting anticoagulation therapy, with particular attention paid to the following: (1) patients who are > 75 years of age; (2) those receiving antiplatelet drugs (such as aspirin or clopidogrel) or nonsteroidal antiinflammatory drugs; (3) those receiving multiple other drug treatments (polypharmacy); (4) those with uncontrolled hypertension; (5) those with a history of bleeding (for example, peptic ulcer or cerebral hemorrhage); and (6) those with a history of poorly controlled anticoagulation therapy.
In the same way that stroke risk stratification schema have been developed and validated,34 improvements in how we identify those at risk of bleeding would be a major advance. Indeed, efforts that reduce the frequency of major warfarin-related bleeding will not only increase the net benefit of anticoagulation therapy but also will facilitate more appropriate and widespread use of thromboprophylaxis, especially in older patients.
Previously, two bleeding risk models have been developed and validated to assist clinicians in balancing the risks and benefits of antithrombotic therapy. The first was the Outpatient Bleeding Risk Index (OBRI), developed by Beyth et al,16 was derived from a original hospital cohort of 556 patients and validated in a prospective cohort of 264 patients. This index considered age > 65 years, prior stroke, prior GI bleed, and any of four comorbidities (recent myocardial infarction, anemia, diabetes, or renal insufficiency) in order to stratify patients into three risk groups. In the original validation cohort, the index predicted major bleeding better than physicians, who estimated the probability of major bleeding no better than that expected by chance. The cumulative incidence at 48 months was 3% in 80 low-risk patients, 12% in 166 intermediate-risk patients, and 53% in 18 high-risk patients. This index was validated by Wells et al17 and Aspinall et al,18 who found reliable prediction of bleeding rates between the intermediate- and high-risk groups. The older population in the study by Aspinall et al18 was more representative of the (usually elderly) patients with AF and, indeed, many of their patients had underlying AF.
The second model was developed by Kuijer et al19 using age > 60 years, gender, and malignancy to stratify patients into three risk groups based on a calculation score with the formula (1.6 x age) + (1.3 x sex) + (2.2 x malignancy). They evaluated this score in an initial cohort of 241 patients with venous thromboembolism and, subsequently, in an independent cohort of 780 patients and found that it was possible to identify a subgroup of patients who would be high risk for bleeding, although clear discrimination was lacking in low-risk groups.
Although these models have some proven validity, they may not include many other known factors that may be predictive of bleeding. Risk is also stratified using lower age groups of 60 to 65 years, while the mean age of populations in whom anticoagulation is commonly used, such as AF, is 75 years. Furthermore, the sample sizes of these populations may not be large enough to be adequately representative of the general population. In real life, many AF patients will also have important comorbidities and concomitant therapies that may increase the risk of bleeding. Thus, there remains a need for a reliable model that addresses the use of warfarin therapy in elderly AF patients.
In this issue of CHEST (see page 1390), Shireman et al20 propose a new contemporary bleeding risk model for elderly patients receiving warfarin, which tries to fully address the difficulties and complexities involved in anticoagulation administration. Their model, which was validated in > 26,000 patients, incorporates eight variables to determine the bleeding risk: age 
70 years, gender, remote bleed, recent bleed, alcohol/drug abuse, diabetes, anemia, and antiplatelet therapy use. They demonstrate bleeding rates of 0.9%, 2.0%, and 5.4% for the low-, moderate-, and high-risk groups, respectively. This study uses a sizeable population, which adds weight and increases the power of the study, thereby validating its use. Clinical trials have been accused of simulating perfect conditions and often involve exclusion of older populations, but in the article by Shireman et al,20 43% of the sample size was > 80 years old and this is certainly more representative of the AF population. Risk factors such as concomitant alcohol use, drug abuse, and gender were taken into account. Differentiation was also made between recent and remote bleeds, and lifetime incidence rather than recent myocardial infarction was considered as a variable. The model by Shireman et al20 was also compared with the OBRI and Kuijer models, with good differentiation between low-, moderate-, and high-risk groups, whereas the Kuijer model was unable to show any difference between the intermediate-risk and high-risk groups. However, an eight-variable risk stratification schema is obviously cumbersome and may limit its applicability. An obvious risk factor that has not been taken into account is the range (or variability) of international normalized ratio (INR) values. We do know that INR values > 3.0 are associated with a greater risk of bleeding and that the risk increases with further increases in the INR. Their study is also limited to a 90-day follow-up period and although a sizeable proportion of warfarin associated bleeds occurred within 90 days, a longer-term follow-up would be desirable to establish a much clearer picture.
Importantly, the burden of AF is high in both community- and hospital-based patients, and the study by Shireman et al20 only includes the latter. This may have a significant impact on risk assessment, as patients admitted to hospitals are invariably more "clinically fragile" and may often bear the burden of polypharmacy, which in itself is a risk factor for bleeding.15 Elderly patients have age-related decreases in creatinine clearance and renal insufficiency that may predispose to uremic gastropathy21 and anemia,22 both of which may increase the risk of bleeding. Since the cohort was predominantly a geriatric one, exclusion of renal impairment may have had a significant impact on risk prediction scores.
The cornerstone of safe and efficacious warfarin use is patient understanding and knowledge of the risks/benefits associated with such therapy, to allow them to manage their treatment effectively in conjunction with physicians and other health professionals. Also, some patients will still decline treatment with warfarin for a wide variety of patient-related reasons despite discussion of the risks and benefits of antithrombotic therapy ("informed dissent").23 Reasons cited include the inconvenience of dosing adjustments and regular blood tests to monitor INR levels; dietary restrictions; the risk of minor and major bleeding; underappreciation or lack of knowledge regarding the risk of stroke; or poor adherence to the treatment regimen.24 Also, many patients with AF possess very limited knowledge of AF as well as its consequences and therapy, and only a minority believed that their doctor had given them "enough information" about their warfarin therapy.2526 The use of educational tools may help in improve patient knowledge and compliance with anticoagulation.25
Risk/benefit stratification schemas are designed to aid management decisions; and for bleeding risk, the new model by Shireman et al20 looks very promising, but further prospective validation data are needed. It is important that these schemas are used as a guide to aid management. Indeed, such management decisions should also be made in the context of assessing individual risk factors for bleeding and hemorrhage, while receiving antithrombotic therapy. As is often the case, many patients who are at the highest risk of a bleed are also at the highest risk of having a stroke, and this clearly poses problems in management. Ultimately, it may still be up to the patient and treating physician to decide each case on an individual basis.
Footnotes
Professor Lip has received funding for research, educational symposia, consultancy, and lecturing from different manufacturers of drugs used for the treatment of atrial fibrillation and thrombosis. He is clinical adviser to the Guideline Development Group writing the United Kingdom National Institute of Health and Clinical Excellence Guidelines on Atrial Fibrillation Management (www.nice.org.uk).
Drs. Kakar and Lane have no conflicts of interest to declare.
References
This article has been cited by other articles:
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  D. A. Lane and G. Y.H. Lip Barriers to Anticoagulation in Patients With Atrial Fibrillation: Changing Physician-Related Factors Stroke, January 1, 2008; 39(1): 7 - 9. [Full Text] [PDF]
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